A5088617435- CAR-T cell therapy research
- Cancer Immunotherapy and Biomarkers
- Immunotherapy and Immune Responses
- Cancer Genomics and Diagnostics
- Virus-based gene therapy research
- Immune Cell Function and Interaction
- Cancer Research and Treatments
- Genetic factors in colorectal cancer
- T-cell and B-cell Immunology
- Monoclonal and Polyclonal Antibodies Research
- CRISPR and Genetic Engineering
- Lymphoma Diagnosis and Treatment
- Ovarian cancer diagnosis and treatment
- Cytomegalovirus and herpesvirus research
- Single-cell and spatial transcriptomics
- HIV Research and Treatment
- Respiratory viral infections research
- Bacteriophages and microbial interactions
- Integrated Circuits and Semiconductor Failure Analysis
- Immunodeficiency and Autoimmune Disorders
- Melanoma and MAPK Pathways
- Advanced biosensing and bioanalysis techniques
- Cutaneous Melanoma Detection and Management
National Cancer Institute
2014-2022
Center for Cancer Research
2016-2022
National Institutes of Health
2016-2022
Ziopharm Oncology (United States)
2019-2021
The University of Texas MD Anderson Cancer Center
2015-2016
Data Harbor (United States)
2015
The University of Texas Medical Branch at Galveston
2006-2007
Abstract Immunotherapies can mediate regression of human tumors with high mutation rates, but responses are rarely observed in patients common epithelial cancers. This raises the question whether these cancers harbor T lymphocytes that recognize mutant proteins expressed by autologous may represent ideal targets for immunotherapy. Using high-throughput immunologic screening gene products identified via whole-exome sequencing, we neoantigen-reactive tumor-infiltrating (TIL) from 62 75 (83%)...
The adoptive cell transfer of select tumor-infiltrating lymphocytes (TILs) for personalized immunotherapy can mediate long-term objective tumor regressions in patients with metastatic melanoma, bile duct, cervix, colon, and breast cancers (1–5). These clinical responses are likely mediated by recognition mutated gene products termed neoantigens because they absent normal tissues. Intratumoral T to identified thus far have been unique the patient, i.e., private mutations not other patients’...
Intratumoral T reg cells are tumor/neoantigen reactive.
Abstract T cells targeting shared oncogenic mutations can induce durable tumor regression in epithelial cancer patients. Such be detected infiltrating lymphocytes, but whether such the peripheral blood of patients with common metastatic is unknown. Using a highly sensitive vitro stimulation and cell enrichment memory from six patients, we identified isolated CD4 + , CD8 mutated KRAS G12D G12V variants, respectively, three In an additional two colon neoantigen-specific SMAD5 MUC4 proteins....
Adoptive cell therapy (ACT) with T cells targeting neoantigens can mediate durable responses in patients metastatic cancer. Cell therapies common shared antigens for epithelial cancers are not yet broadly available. Here, we report the identification and characterization one patient of T-cell receptors (TCRs) recognizing mutated p53 p.R175H, which is among a subset Tumor-infiltrating lymphocytes were screened recognition colorectal HLA-A*0201-restricted p.R175H was identified, minimal...
Abstract Purpose: This was a study prospectively evaluating intratumoral T-cell responses to autologous somatic mutated neoepitopes expressed by human metastatic ovarian cancers. Patients and Methods: Tumor-infiltrating lymphocytes (TIL) were expanded from resected cancer metastases, which analyzed whole-exome transcriptome sequencing identify mutations. All neoepitopes, independent of prediction algorithms, in antigen-presenting cells then cocultured with TIL fragment cultures. Secretion...
Abstract Purpose: To activate and propagate populations of γδ T cells expressing polyclonal repertoire γ δ T-cell receptor (TCR) chains for adoptive immunotherapy cancer, which has yet to be achieved. Experimental Design: Clinical-grade artificial antigen-presenting (aAPC) derived from K562 tumor were used as irradiated feeders expand human clinical scale. These tested proliferation, TCR expression, memory phenotype, cytokine secretion, killing. Results: proliferation was dependent upon...
Adoptive transfer of tumor-infiltrating lymphocytes (TIL) fails to consistently elicit tumor rejection. Manipulation intrinsic factors that inhibit T cell effector function and neoantigen recognition may therefore improve TIL therapy outcomes. We previously identified the cytokine-induced SH2 protein (CISH) as a key regulator functional avidity in mice. Here, we investigate mechanistic role CISH regulating human solid tumors demonstrate CRISPR/Cas9 disruption enhances response checkpoint...
Respiratory syncytial virus (RSV) is a common cause of respiratory tract infections in infants and the elderly. Like many other pH-independent enveloped viruses, RSV thought to enter at cell surface, independently endocytic pathways. We have used targeted small interfering RNA (siRNA) library identify key cellular genes involved cytoskeletal dynamics endosome trafficking that are important for infection. Surprisingly, infection was potently inhibited by siRNAs targeting associated with...
This pilot feasibility clinical trial evaluated the coadministration of vemurafenib, a small-molecule antagonist BRAFV600 mutations, and tumor-infiltrating lymphocytes (TIL) for treatment metastatic melanoma.A tumor was resected growth TILs, patients were treated with vemurafenib 2 weeks, followed by resection second lesion. Patients then received nonmyeloablative preconditioning regimen, infusion autologous high-dose interleukin-2 administration. Vemurafenib restarted at time TIL continued...
Neoantigens unique to each patient's tumor can be recognized by autologous T cells through their T-cell receptor (TCR) but the low frequency and/or terminal differentiation of mutation-specific in tumors limit utility as adoptive therapies. Transfer TCR genes into younger from peripheral blood with a high proliferative potential could obviate this problem. We generated rapid, cost-effective strategy genetically engineer cancer patient TCRs using clinical Sleeping Beauty...
Adoptive immunotherapy infusing T cells with engineered specificity for CD19 expressed on B-cell malignancies is generating enthusiasm to extend this approach other hematological malignancies, such as acute myelogenous leukemia (AML).CD123, or interleukin 3 receptor alpha, overexpressed most AML and some lymphoid lymphocytic (ALL), has been an effective target expressing chimeric antigen receptors (CARs).The prototypical CAR encodes a V H L from one monoclonal antibody (mAb), coupled...
T cells modified with chimeric antigen receptors (CARs) targeting CD19 demonstrated clinical activity against some B-cell malignancies. However, this is often accompanied by a loss of normal CD19+ B and humoral immunity. Receptor tyrosine kinase-like orphan receptor-1 (ROR1) expressed on sub-populations malignancies solid tumors, but not healthy or post-partum tissues. Thus, adoptive transfer specific for ROR1 has potential to eliminate tumor spare To test hypothesis, we developed CARs in...
Engineered T cells expressing tumor-specific T-cell receptors (TCRs) are emerging as a mode of personalized cancer immunotherapy that requires identification TCRs against the products known driver mutations and novel in timely fashion. We present nonviral non-next-generation sequencing platform for rapid, efficient neoantigen-specific TCR evaluation does not require use recombinant cloning techniques. The includes an innovative method TCRα detection using Sanger sequencing, pairings TCRα/β...
Adoptive T cell therapies (ACT) have been curative for a limited number of cancer patients. The sensitization cells to killing may expand the benefit these more To this end, we use three-step approach identify genes that disfavor immunity. First, profile gene transcripts upregulated by under selection pressure from killing. Second, potential tumor targets and pathways using signaling pathway activation libraries genome-wide loss-of-function CRISPR-Cas9 screens. Finally, implement...
2547 Background: Solid tumors present driver mutations in KRAS, TP53, and EGFR genes on their surface the context of human leukocyte antigen (HLA) molecules to T-cell receptors (TCRs) expressed by T cells. Non-viral genetic engineering patient cells with Sleeping Beauty transposon/transposase system can generate mutation-reactive TCR-T Methods: This is a first-in-human phase 1/2 study autologous cell therapy for patients non-small lung (NSCLC), colorectal, endometrial, pancreatic, ovarian...
One of the most important steps in a productive viral infection is when virus fuses to cell membrane and delivers its genome into cytosol. This dynamic event mediated by interactions between specific envelope proteins with their cell-bound receptors. process exemplified Moloney murine leukemia (Mo-MLV) where protein interaction receptor, mCAT-1, leads virus−cell fusion cells. Here, fluorescent nanoparticles (NPs) were coated Mo-MLV derived membranes (Mo-NPs) extrusion. Electron microscopy...
Abstract While neoantigen-specific tumor infiltrating lymphocytes (TIL) can be derived from in antigen-expressing tumors, their adoptive transfer fails to consistently elicit durable regression. There has been much focus on the role of activation/exhaustion markers such as PD1, CD39 and TOX TIL senescence. We found these were inversely expressed Cytokine-Induced SH2 protein (CISH), a negative regulator TCR signaling immunity mice. To evaluate physiological CISH human we developed...
Abstract While neoantigen-specific tumor infiltrating lymphocytes (TIL) can be derived from in antigen-expressing tumors, their adoptive transfer fails to consistently elicit durable regression. There has been much focus on the role of activation/exhaustion markers such as PD1, CD39 and TOX TIL senescence. We found these were inversely expressed Cytokine-Induced SH2 protein (CISH), a negative regulator TCR signaling immunity mice. To evaluate physiological CISH human we developed...
<h3>Background</h3> Neoantigen-specific T cells isolated from tumors have shown promise clinically but fail to consistently elicit durable tumor regression. Expression of the intracellular checkpoint CISH is elevated in human infiltrating lymphocytes (TIL) and has been inhibit neoantigen reactivity murine TIL. <h3>Methods</h3> To explore function we developed a CRISPR/Cas9-based strategy knockout (KO) with high-efficiency (>90%) without detectable off-target editing. <h3>Results</h3> KO...
Meeting abstracts Adoptive cell therapy with T cells bearing mutation specific receptors (TCR) can be an effective method for treating metastatic cancers. The objective of this study was to identify reactive in the circulation patients different types
Somatic mutations expressed by the tumor can serve as neoantigens for autologous T cells. Tumor infiltrating lymphocytes (TIL) with varying degrees of neoantigen-reactivity infused treatment melanoma resulted in 50% overall objective response and 20% complete rates. A largely oligoclonal population ERBB2IPE805G mutated neoantigen-specific cells a long-term, ongoing partial regression metastatic cholangiocarcinoma suggesting that infusion selected mutation-reactive TIL could be efficacious...